NM_147127.5:c.52C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_147127.5(EVC2):c.52C>T(p.Leu18Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,505,760 control chromosomes in the GnomAD database, including 15,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 2994 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12597 hom. )

Consequence

EVC2
NM_147127.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0250

Publications

10 publications found

Variant links:

Genes affected

EVC2 (HGNC:19747): (EvC ciliary complex subunit 2) This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

EVC2 Gene-Disease associations (from GenCC):

acrofacial dysostosis, Weyers type
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine

EVC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004922539).

BP6

Variant 4-5708462-G-A is Benign according to our data. Variant chr4-5708462-G-A is described in ClinVar as Benign. ClinVar VariationId is 262618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC2	NM_147127.5 link	c.52C>T	p.Leu18Phe	missense_variant	Exon 1 of 22	ENST00000344408.10	NP_667338.3	Q86UK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC2	ENST00000344408.10 link	c.52C>T	p.Leu18Phe	missense_variant	Exon 1 of 22	1	NM_147127.5	ENSP00000342144.5	Q86UK5-1
EVC2	ENST00000310917.6 link	c.-13+367C>T		intron_variant	Intron 1 of 21	1		ENSP00000311683.2	Q86UK5-2
EVC2	ENST00000475313.5 link	n.-13+367C>T		intron_variant	Intron 1 of 22	1		ENSP00000431981.1	A0A0C4DGE7
EVC2	ENST00000509670.1 link	n.-106-322C>T		intron_variant	Intron 1 of 22	1		ENSP00000423876.1	E9PFT2

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

26979

AN:

151866

Hom.:

2982

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.160

GnomAD2 exomes

AF:

0.152

AC:

15220

AN:

100284

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.291

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.0984

Gnomad EAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.128

AC:

173268

AN:

1353784

Hom.:

12597

Cov.:

AF XY:

0.129

AC XY:

85908

AN XY:

667562

show subpopulations

African (AFR)

AF:

0.311

AC:

8587

AN:

27608

American (AMR)

AF:

0.208

AC:

6864

AN:

33062

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

2487

AN:

24084

East Asian (EAS)

AF:

0.244

AC:

7790

AN:

31934

South Asian (SAS)

AF:

0.187

AC:

14228

AN:

76252

European-Finnish (FIN)

AF:

0.122

AC:

4065

AN:

33296

Middle Eastern (MID)

AF:

0.113

AC:

455

AN:

4014

European-Non Finnish (NFE)

AF:

0.114

AC:

121234

AN:

1067036

Other (OTH)

AF:

0.134

AC:

7558

AN:

56498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

8176

16352

24527

32703

40879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4694

9388

14082

18776

23470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.178

AC:

27045

AN:

151976

Hom.:

2994

Cov.:

AF XY:

0.179

AC XY:

13287

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.302

AC:

12526

AN:

41490

American (AMR)

AF:

0.189

AC:

2894

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

359

AN:

3460

East Asian (EAS)

AF:

0.177

AC:

900

AN:

5086

South Asian (SAS)

AF:

0.192

AC:

925

AN:

4824

European-Finnish (FIN)

AF:

0.113

AC:

1193

AN:

10600

Middle Eastern (MID)

AF:

0.113

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.112

AC:

7598

AN:

67926

Other (OTH)

AF:

0.165

AC:

349

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1070

2139

3209

4278

5348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0792

Hom.:

153

Bravo

AF:

0.187

TwinsUK

AF:

0.115

AC:

428

ALSPAC

AF:

0.118

AC:

455

ExAC

AF:

0.0976

AC:

2186

Asia WGS

AF:

0.237

AC:

824

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 14, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ellis-van Creveld syndrome

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Curry-Hall syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-0.025

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.85

REVEL

Benign

0.24

Sift

Benign

0.075

Sift4G

Uncertain

0.036

Polyphen

0.72

Vest4

0.029

MPC

0.021

ClinPred

0.0030

GERP RS

-1.8

PromoterAI

-0.091

Neutral

(source)

Varity_R

0.063

gMVP

0.12

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over